1. Field of the Invention
The invention relates to the field of pharmacologically active 2.beta., 16.beta.-bis-piperidino-androstanes, and more specifically, to the use of bis-quaternary ammonium compounds of derivatives of said androstanes as neuromuscular blocking agents.
2. Description of the Prior Art, and Other Information
From British Pat. No. 1,138,605, incorporated herein, (see also U.S. Pat. No. 3,553,212) it is known that certain bis-quaternary ammonium compounds of 2.beta.,16.beta.-bis-piperidino-3.alpha.,17.beta.-dihydroxy-5.alpha.-andro stane-3.alpha.,17.beta.-diesters are highly active neuromuscular blocking agents.
A similar observation was made in Journal of Med. Chemistry 16, 1116, 1973, incorporated herein, but besides bis-quaternary ammonium compounds of 2.beta.,16.beta.,bis-piperidino-3.alpha.,17.beta.-dihydroxy-5.alpha.-andro stane-3.alpha.,17.beta.-diesters, also 16-mono-quaternary ammonium compounds of these diesters are described to have the same order of potency as the corresponding bis-quaternary compounds.
16-Mono quaternary- as well as 2,16-bis quaternary ammonium compounds of 2.beta.,16.beta.-bis-piperidino-3.alpha.-hydroxy-5.alpha.-androstane-3.alp ha.-esters are further known from the British Pat. No. 1,454,749, incorporated herein (see also U.S. Pat. No. 3,872,091).
It has been found that the 16-mono-quaternary ammonium derivatives of the said mono- and diesters in question turned out to be even more interesting compounds than the corresponding bis-quaternary ammonium compounds because of their quicker onset and shorter duration of action, which offer under most surgical conditions pronounced advantages, and because of their lack of cardiovascular side-effects.
However, in contrast to the bis-quaternary compounds, the 16-mono-quaternary ammonium compounds of 2.beta.,16.beta.-bis-piperidino-3.alpha.,17.beta.-dihydroxy-5.alpha.-andro stane 3.alpha.,17.beta.-diesters and the corresponding 17.beta.-unsubstituted 3.alpha.-mono-esters start to decompose almost immediately when dissolved in water and hence cannot be used in aqueous injection preparations.
Since neuromuscular blocking agents are mainly used in surgical treatments and are administered through injection, it would be a definite advance in the art to possess a stable aqueous injection preparation containing the 16-mono-quaternary ammonium compound of 2.beta.,16.beta.-bis-piperidino-3.alpha.,17.beta.-dihydroxy-5.alpha.-andro stane 3.alpha.,17.beta.-diesters or of the corresponding 17.beta.-unsubstituted-3.alpha.-mono-esters.
Surprisingly, it has now been found that the pharmaceutically acceptable acid addition salts of the 16.beta.-mono-quaternary ammonium derivatives of either 2.beta.,16.beta.-bis-piperidino-3.alpha.,17.beta.-dihydroxy-5.alpha.-andro stane 3.alpha.,17.beta.-di-lower aliphatic esters or 2.beta., 16.beta.-bis-piperidino-3.alpha.-hydroxy-5.alpha.-androstane-3.alpha.-lowe r aliphatic esters are relatively stable in aqueous solutions to the extent that they can provide stable aqueous injection preparations.
Particularly preferred are the acid addition salts of compounds of the general formula (I): ##STR1## wherein: (a) R is hydrogen or the moiety --OR.sub.2 ;
(b) R.sub.1 and R.sub.2 each represent an unsubstituted acyl group derived from a lower aliphatic carboxylic acid of one to about six carbons; PA1 (c) ALK is an unsubstituted alkyl, alkenyl or alkynyl group of one to four carbon atoms; and PA1 (d) A.sup..crclbar. represents a pharmaceutically acceptable organic or inorganic anion.